ABSTRACT Spinal cord injury (SCI) causes devastating neurological deficits and long-term disability due to axon regeneration failure. Despite recent progress, successful strategies to promote repair and functional recovery after SCI remain elusive. This may be because multiple intrinsic neuronal and extrinsic non-neuronal mechanisms must be targeted simultaneously to promote successful axon regeneration. For example, severed axons need to be stimulated to regrow long distances through a hostile lesion environment and even then, optimal functional recovery is unlikely unless regenerated axons are remyelinated. Thus, an ideal treatment would be delivered as a post-injury medication and would affect each phase of repair. Using whole transcriptome sequencing and bioinformatic analysis followed by gain- and loss-of-function experiments, we recently discovered that Cacna2d2, the gene encoding the Alpha2delta2 subunit of voltage-gated calcium channels, functions as a developmental switch that limits axon growth and regeneration in adult sensory neurons. Alpha2delta2 pharmacological blockade through systemic administration of Gabapentinoids (e.g., drugs used clinically to treat various neurological disorders) promotes axon regeneration after SCI in adult mice. Our preliminary data suggest that giving Gabapentinoids early after SCI promotes functional recovery. However, the mechanisms of recovery are not known and it is therefore critical to investigate the cellular and molecular mechanisms underpinning neurological recovery in SCI mice receiving Gabapentinoids. While neurons are thought to be the site of action for Gabapentinoids, our preliminary data indicate that extrinsic non- neuronal mechanisms are also affected by Gabapentinoids. Accordingly, experiments in Aim 1 will use mouse genetics, tissue clearing methods, three-dimensional imaging of the unsectioned spinal cord and chronic in vivo multiphoton microscopy to identify structural and functional changes in astrocyte scar formation caused by Gabapentinoids. The primary goal is to determine what changes in astrocyte reactivity permit axon regeneration into and beyond the lesion site in animals receiving Gabapentinoids. Aim 2 will explore the mechanisms by which Gabapentinoids release the tips of severed axons, also called dystrophic endballs, from entrapment at the lesion site, thereby creating favorable conditions for successful axon regeneration. SCI is also known to cause progressive demyelination in both experimental murine models and humans, leading to the axonal dysfunction and degeneration that contributes to loss of function. Using a combination of electron microscopy, immunohistochemical, electrophysiological and imaging techniques, Aim 3 will test whether Gabapentinoids promote myelin repair after SCI. Given that our treatment strategy can be readily translated across different species, implementation of Gabapentinoids-based strategies is well positioned to leverage significant improvement of neurological outcome following SCI.